Biology subjects

Ding, H.

Publications and source records attributed to Ding, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Identification and Pharmacological Targeting of Treatment-Resistant, Stem-like Breast Cancer Cells for Combination Therapy

Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential--often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulation in vivo without noticeable cytotoxicity. Moreover, sequential cycles of albendazole and paclitaxel--a commonly used chemotherapeutic --displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations. Statement of significanceNetwork-based approaches, as shown in a study on metastatic breast cancer, can develop effective combinatorial therapies targeting complementary subpopulations. By analyzing scRNA-seq data and using clinically relevant drugs, researchers identified and depleted chemoresistant Cancer Stem-Like Cells, enhancing the efficacy of standard chemotherapies.

systems biology↗

bioRxiv2023

A high-performance brain-sentence communication designed for logosyllabic language

Many severe neurological diseases, such as stroke and amyotrophic lateral sclerosis, can impair or destroy the ability of verbal communication. Recent advances in brain-computer interfaces (BCIs) have shown promise in restoring communication by decoding neural signals related to speech or motor activities into text. Existing research on speech neuroprosthesis has predominantly focused on alphabetic languages, leaving a significant gap of logosyllabic languages such as Mandarin Chinese which are spoken by more than 15% of the world population. Logosyllabic languages pose unique challenges to brain-to-text decoding due to extended character sets (e.g., 50,000+ for Mandarin Chinese) and complex mapping between characters and pronunciation. To address these challenges, we established a speech BCI designed for Mandarin, decoding speech-related stereoelectroencephalography (sEEG) signals into coherent sentences. We leverage the unique acoustic features of Mandarin Chinese syllables, constructing prediction models for syllable components (initials, tones, and finals), and employ a language model to resolve pronunciation to character ambiguities according to the semantic context. This method leads to a high-performance decoder with a median character accuracy of 71.00% over the full character set, demonstrating huge potentials for clinical application. To our knowledge, we are the first to report brain-to-sentence decoding for logosyllabic languages over full character set with a large intracranial electroencephalography dataset.

neuroscience↗

bioRxiv2023

A Spatiotemporal and Machine-Learning Platform Accelerates the Manufacturing of hPSC-derived Esophageal Mucosa

Human pluripotent stem cell-derived tissue engineering offers great promise in designer cell-based personalized therapeutics. To harness such potential, a broader approach requires a deeper understanding of tissue-level interactions. We previously developed a manufacturing system for the ectoderm-derived skin epithelium for cell replacement therapy. However, it remains challenging to manufacture the endoderm-derived esophageal epithelium, despite both possessing similar stratified structure. Here we employ single cell and spatial technologies to generate a spatiotemporal multi-omics cell atlas for human esophageal development. We illuminate the cellular diversity, dynamics and signal communications for the developing esophageal epithelium and stroma. Using the machine-learning based Manatee, we prioritize the combinations of candidate human developmental signals for in vitro derivation of esophageal basal cells. Functional validation of the Manatee predictions leads to a clinically-compatible system for manufacturing human esophageal mucosa. Our approach creates a versatile platform to accelerate human tissue manufacturing for future cell replacement therapies to treat human genetic defects and wounds.

developmental biology↗

bioRxiv2023

CircSMAD3 represses VSMC phenotype switching and neointima formation via promoting hnRNPA1 ubiquitination degradation

AimsCircular RNAs (circRNAs) are novel regulatory RNAs with high evolutionary conservation and stability, making them attractive therapeutic agents for various vascular diseases. SMAD family is a downstream mediator of the canonical TGF{beta} signalling pathway and has been considered a critical regulator in vascular injury. However, the role of circRNAs derived from the SMAD family members in vascular physiology remains unclear. Therefore, this study aimed to identify a functional circRNA derived from the SMAD family and elucidate its potential as an effective therapeutic agent for vascular proliferative diseases. Methods and ResultsWe initially identified potential functional circRNAs originating from the SMAD family using integrated transcriptome screening. circSMAD3, derived from the SMAD3 gene, was identified to be significantly downregulated in vascular injury and atherosclerosis. Transcriptome analysis was conducted to comprehensively illustrate the pathways modulated by circRNAs. Functionally, circSMAD3 repressed VSMC proliferation and phenotype switching in vitro evidenced by morphological assays and ameliorated arterial injury-induced neointima formation in vivo. Mechanistically, circSMAD3 interacted with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) within the nucleus, enhanced its interaction with E3 ligase WD repeat domain 76 (WDR76) to promote hnRNPA1 ubiquitination degradation, facilitated p53 pre-RNA splicing, activated p53{gamma} signalling pathway, and finally suppressed VSMC proliferation and phenotype switching. ConclusionOur study identifies circSMAD3 as a novel epigenetic regulator that suppresses VSMC proliferation and phenotype switching, thereby attenuating vascular remodelling and providing a new circRNA-based therapeutic strategy for cardiovascular diseases.

molecular biology↗

bioRxiv2023

Quantitative label free mass spectrometry reveals content and signaling differences between neonatal and adult platelets

Background and ObjectiveRecent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions. This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets. MethodsWe isolated resting umbilical cord blood-derived platelets from healthy full term neonates (n=9) and resting blood platelets from healthy adults (n=7), and compared protein and phosphoprotein contents using data independent acquisition mass spectrometry. ResultsWe identified 4745 platelet proteins with high confidence across all samples. Adult and neonatal platelets clustered separately by principal component analysis. Adult platelets were significantly enriched for immunomodulatory proteins, including {beta}2 microglobulin and CXCL12, whereas neonatal platelets were enriched for ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched for phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched for phosphorylated proteins involved in insulin growth factor signaling. ConclusionsUsing state-of-the-art mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation compared with adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of a molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants.

cell biology↗

bioRxiv2023

Multitask Learning of Longitudinal Circulating Biomarkers and Clinical Outcomes: Identification of Optimal Machine-Learning and Deep-Learning Models

Many circulating biomarkers are assessed at different time intervals during clinical studies. Despite of the success of standard joint models in predicting clinical outcomes using low-dimensional longitudinal data (1-2 biomarkers), significant computational challenges are encountered when applying these techniques to high-dimensional biomarker datasets. Modern machine- or deep-learning models show potential for multiple biomarker processes, but systematic evaluations and applications to high-dimensional data in the clinical settings have yet to be reported. We aimed to enhance the scalability of joint modeling and provide guidance on optimal approaches for high-dimensional biomarker data and outcomes. We evaluated multiple deep-learning and machine-learning models using 24 clinical biomarkers and survival data from the SQUIRE trial, a phase 3 randomized clinical trial investigating necitumumab and standard gemcitabine/cisplatin treatment in patients with squamous non-small-cell lung cancer (NSCLC). Overall, we confirmed that longitudinal models enabled more accurate prediction of patients survival compared to those solely based on baseline information. Coupling multivariate functional principal component analysis (MFPCA) with Cox regression (MFPCA-Cox) provided the highest predictive discrimination and accuracy for the NSCLC patients with AUC values of 0.7 - >0.8 at various landmark time points and prediction timeframes, outperforming recent advanced Transformer and convolutional neural network deep-learning algorithms (TransformerJM and Match-Net, respectively). In conclusion, we identified that MFPCA-Cox represents a robust and versatile joint modeling algorithm for high-dimensional biomarker longitudinal data with irregular and missing data, capturing complex relationships within the data, yielding accurate predictions for both longitudinal biomarkers and survival outcomes, and gaining insights into the underlying dynamics.

pharmacology and toxicology↗

bioRxiv2023

VACmap: an accurate long-read aligner for unraveling complex structural variations

Inversions, duplications, and other critical medically challenging variations are often ignored by routine genetic analyses. This is due to the complexity of these alleles but also because of the inability to accurately align them with state-of-the-art methods. We introduce VACmap, a novel non-linear long-read mapping method designed to improve detection of these difficult genomic regions, including critical genes like LPA and GBA1, which are significant risk factors for cardiovascular disease and Parkinsons disease, respectively.

bioinformatics↗

bioRxiv2023

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We have previously shown that KEAP1 mutant tumors have increased glutamine consumption to support the metabolic rewiring associated with NRF2 activation. Here, using patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the novel glutamine antagonist DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumor growth by inhibiting glutamine-dependent nucleotide synthesis and promoting anti-tumor CD4 and CD8 T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we discover that DRP-104 reverses T cell exhaustion and enhances the function of CD4 and CD8 T cells culminating in an improved response to anti-PD1 therapy. Our pre-clinical findings provide compelling evidence that DRP-104, currently in phase 1 clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer. Furthermore, we demonstrate that by combining DRP-104 with checkpoint inhibition, we can achieve suppression of tumor intrinsic metabolism and augmentation of anti-tumor T cell responses.

cancer biology↗

bioRxiv2023

The maize PLASTID TERMINAL OXIDASE (PTOX) gene controls the carotenoid content of kernels.

O_LICarotenoids perform a broad range of important functions in humans; therefore, carotenoid biofortification of maize (Zea mays L.), one of the most highly produced cereal crops worldwide, would have a global impact on human health. C_LIO_LIPLASTID TERMINAL OXIDASE (PTOX) genes play an important role in carotenoid metabolism; however, the possible function of PTOX in carotenoid biosynthesis in maize has not yet been explored. In this study, we identified the maize PTOX gene ZmPTOX1 by forward genetic screening. C_LIO_LIWhile most higher plant species possess a single copy of the PTOX gene, maize carries two tandemly duplicated copies of ZmPTOX. Characterization of Zmptox1 mutants revealed that disrupting one copy of ZmPTOX1 was enough to impair carotenoid biosynthesis, indicating that ZmPTOX1 is essential for carotenoid biosynthesis in maize kernels. Remarkably, overexpression of ZmPTOX1 significantly improved the content of carotenoids, especially {beta}-carotene (provitamin A), which was increased by ~3-fold, in maize kernels. C_LIO_LIOverall, our study shows that ZmPTOX1 plays a crucial role in carotenoid biosynthesis in maize kernels and suggests that fine-tuning the expression of this gene could improve the nutritional value of cereal grains. C_LI

plant biology↗

bioRxiv2023

Conformations of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoproteins in Detergents and Styrene-Maleic Acid Lipid Particles (SMALPs)

The mature human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer, which consists of non-covalently associated gp120 exterior and gp41 transmembrane subunits, mediates virus entry into cells. The pretriggered (State-1) Env conformation is the major target for broadly neutralizing antibodies (bNAbs), whereas receptor-induced downstream Env conformations elicit immunodominant, poorly neutralizing antibody (pNAb) responses. To examine the contribution of membrane anchorage to the maintenance of the metastable pretriggered Env conformation, we compared wild-type and State-1-stabilized Envs solubilized in detergents or in styrene-maleic acid (SMA) copolymers. SMA directly incorporates membrane lipids and resident membrane proteins into lipid nanodiscs (SMALPs). The integrity of the Env trimer in SMALPs was maintained at both 4{degrees}C and room temperature. By contrast, Envs solubilized in Cymal-5, a non-ionic detergent, were unstable at room temperature, although their stability was improved at 4{degrees}C and after incubation with the entry inhibitor BMS-806. Envs solubilized in ionic detergents were relatively unstable at either temperature. Comparison of Envs solubilized in Cymal-5 and SMA at 4{degrees}C revealed subtle differences in bNAb binding to the gp41 membrane-proximal external region (MPER), consistent with these distinct modes of Env solubilization. Otherwise, the antigenicity of the Cymal-5- and SMA- solubilized Envs was remarkably similar, both in the absence and presence of BMS-806. However, both solubilized Envs were recognized differently from the mature membrane Env by specific bNAbs and pNAbs. Thus, detergent-based and detergent-free solubilization at 4{degrees}C alters the pretriggered membrane Env conformation in consistent ways, indicating that loss of Env association with the membrane results in default state(s). IMPORTANCEThe human immunodeficiency virus (HIV-1) envelope glycoproteins (Envs) in the viral membrane mediate virus entry into the host cell and are targeted by neutralizing antibodies elicited by natural infection or vaccines. Detailed studies of membrane proteins rely on purification procedures that allow the proteins to maintain their natural conformation. In this study, we show that a styrene-maleic acid (SMA) copolymer can extract HIV-1 Env from a membrane without the use of detergents. The Env in SMA is more stable at room temperature than Env in detergents. The purified Env in SMA maintains many but not all of the characteristics expected of the natural membrane Env. Our results underscore the importance of the membrane environment to the native conformation of HIV-1 Env. Purification methods that bypass the need for detergents could be useful tools for future studies of HIV-1 Env structure and its interaction with receptors and antibodies.

microbiology↗

bioRxiv2023

E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension

RationaleRare genetic variants and genetic variation at loci in an enhancer in SRY-Box Transcription Factor 17 (SOX17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutation in SOX17 in PAH pathogenesis has not been reported. ObjectivesTo investigate the role of SOX17 deficiency in pulmonary hypertension (PH) development. MethodsHuman lung tissue and endothelial cells (ECs) from IPAH patients were used to determine the expression of SOX17. Tie2Cre-mediated and EC-specific deletion of Sox17 mice were assessed for PH development. Single-cell RNA sequencing analysis, human lung ECs, and smooth muscle cell culture were performed to determine the role and mechanisms of SOX17 deficiency. A pharmacological approach was used in Sox17 deficiency mice for therapeutic implication. Measurement and Main ResultsSOX17 expression was downregulated in the lungs and pulmonary ECs of IPAH patients. Mice with Tie2Cre mediated Sox17 knockdown and EC-specific Sox17 deletion developed spontaneously mild PH. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced PH in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and anti-apoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP signaling. E2F Transcription Factor 1 (E2F1) signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction and PH development. ConclusionsOur study demonstrated that endothelial SOX17 deficiency induces PH through E2F1 and targeting E2F1 signaling represents a promising approach in PAH patients.

physiology↗

bioRxiv2023

Causal inference during closed-loop navigation: parsing of self- and object-motion

A key computation in building adaptive internal models of the external world is to ascribe sensory signals to their likely cause(s), a process of Bayesian Causal Inference (CI). CI is well studied within the framework of two-alternative forced-choice tasks, but less well understood within the cadre of naturalistic action-perception loops. Here, we examine the process of disambiguating retinal motion caused by self- and/or object-motion during closed-loop navigation. First, we derive a normative account specifying how observers ought to intercept hidden and moving targets given their belief over (i) whether retinal motion was caused by the target moving, and (ii) if so, with what velocity. Next, in line with the modeling results, we show that humans report targets as stationary and steer toward their initial rather than final position more often when they are themselves moving, suggesting a misattribution of object-motion to the self. Further, we predict that observers should misattribute retinal motion more often: (i) during passive rather than active self-motion (given the lack of an efference copy informing self-motion estimates in the former), and (ii) when targets are presented eccentrically rather than centrally (given that lateral self-motion flow vectors are larger at eccentric locations during forward self-motion). Results confirm both of these predictions. Lastly, analysis of eye-movements show that, while initial saccades toward targets are largely accurate regardless of the self-motion condition, subsequent gaze pursuit was modulated by target velocity during object-only motion, but not during concurrent object- and self-motion. These results demonstrate CI within action-perception loops, and suggest a protracted temporal unfolding of the computations characterizing CI.

neuroscience↗

bioRxiv2023

Insulin determines the effects of TGF-beta on HNF4alpha transcription and epithelial-to-mesenchymal transition in hepatocytes

To date, epithelial-to-mesenchymal transition (EMT) has been observed in cultured hepatocytes, but not in vivo. TGF-{beta} is supposed to initiate EMT in hepatocytes by inhibiting HNF4 through the SMAD2/3 complex. We report that TGF-{beta} does not directly inhibit HNF4, but contributes to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CBP/p300 to the HNF4 promoter. The recruitment of CBP/p300 is indispensable for C/EBPa binding, another essential requirement for constitutive HNF4 expression in hepatocytes. In contrast to the observed induction of HNF4, SMAD2/3 inhibits C/EBP transcription. Therefore, long-term TGF-{beta} incubation results in C/EBP depletion, which abrogates HNF4 expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBP promoter is abolished by insulin. Thus, maintaining a high insulin concentration in culture medium ensures constitutive HNF4 and thereby prevents TGF-{beta}-induced hepatocyte EMT. Furthermore, insulin inhibits TGF-{beta}-induced SMAD2/3 binding to the promoters of core EMT transcription factors e.g., SNAI1. SNAI1 transcription requires both SMAD2/3 and FOXO1 in nuclei. Insulin inhibits SNAI1 transcription through impeding SMAD2/3 binding to its promoter and inducing FOXO1 phosphorylation. Hence, insulin is the key factor that prevents TGF-{beta}-induced EMT in hepatocytes.

cell biology↗

bioRxiv2022

Dysregulated Expression of Circadian Genes in Lymphoblastoid Cells of Patients with ASD

Patients with Autism Spectrum Disorder (ASD) often exhibit disturbances in sleep, metabolism, and immune system. The molecular mechanisms for these clinical features in ASD are currently unknown. We demonstrated that circadian genes in the cells of patients with ASD often are dysregulated compared to controls. The dysregulation of circadian genes was reflected in two different ways: (1) abnormal levels of expression; and (2) a change of gene-gene association pattern in the co-expression network. We also observed a link between abnormal expression of circadian genes in lymphoblastoid cells with sleep phenotypes in patients with ASD. Our results suggest that circadian genes and circadian rhythms might play critical roles in the pathogenesis of ASD.

pathology↗

bioRxiv2022

Serotonergic Modulation of Spinal Circuitry Restores Motor Function after Chronic Spinal Cord Injury

Electrical stimulation of the nervous system has been employed to enhance the recovery of motor function produced by use-dependent rehabilitation, which is the current gold standard of treatment, following spinal cord injury. However, the therapeutic effects almost always rely on the sustained activation of muscles or neurons, making the benefits largely contingent on continued delivery of stimulation. In the present study, we describe a neuromodulatory intervention that combined intraspinal delivery of serotonergic agonists with use-dependent rehabilitation to restore motor function after a chronic moderate-to-severe cervical contusion in rats that produces impairments in upper-limb movements and dexterity. We show that targeted delivery of quipazine, a broad-spectrum serotonergic agonist, caudal to the lesion increased the effectiveness of physical rehabilitation, leading to substantially improved motor-recovery outcomes in severely-injured, but not moderately-injured, animals. Delivery of quipazine significantly augmented recovery of skilled reach and grasp movements after a severe injury, but moderately-injured animals received no additional benefit from quipazine over physical rehabilitation alone. This difference was perhaps due to a greater loss of serotonin after a severe injury and a resulting environment in which exogenously-applied serotonin can improve circuit function. Our experiments highlight an important role for serotonin in restoration of motor function that is dependent on the severity of the spinal cord injury. They also allude to a potential role for residual serotonin as a biomarker of injury severity. Remarkably, quipazine-mediated behavioral improvements persisted for weeks after termination of neuromodulator delivery, signaling repair of severely-damaged adult spinal circuitry that drives lasting motor recovery. Significance StatementWe describe a neuromodulatory intervention that combined intraspinal delivery of serotonergic agonists with use-dependent physical rehabilitation, which is the current standard of treatment, to promote motor recovery after a chronic moderate-to-severe spinal-contusion injury. Our results show that targeted delivery of serotonergic agonists caudal to the lesion increased the effectiveness of use-dependent rehabilitation, leading to substantially improved motor-recovery outcomes in severely-injured, but not moderately-injured, animals. Notably, therapeutic gains persisted for weeks after termination of neuromodulator delivery--a finding that is both unique and clinically relevant--signaling plasticity induction and repair in chronically-damaged adult spinal circuitry. Our experiments provide important insights into serotonergic modulation of spinal circuitry and highlight a potential role for residual serotonin as a neurochemical biomarker of injury severity.

neuroscience↗

bioRxiv2022

Human adenovirus infection induces the overexpression of CLOCK protein in human lymphoblast cells

Circadian rhythms are biological processes that regulate metabolism, the immune system, hormones, behaviors, and other various biological processes in organisms. The molecular underpinning of circadian rhythms is a group of genes which regulate each other in transcription-translation feedback loops as an internal molecular clock in cells. Many factors can affect the circadian clock. Viruses, such as hepatitis virus, influenza virus, human immunodeficiency virus were reported to interplay with circadian rhythms in the host or cell level. Up to date, the relationship between viruses and circadian rhythms and its significance in biology, pharmacology and clinic are not entirely understood. We here report that human adenovirus infection could regulate circadian rhythms in cells. We found that human adenovirus infection induced protein overexpression of a core circadian gene CLOCK in human lymphoblast cells. The conditioned medium collected from the infected lymphoblast cell culture was able to infect other lymphoblast cell lines and induced CLOCK overexpression in them. In contrast to the previous studies that showed viral infections dampened the circadian oscillation, we found that the human adenovirus infection increased the amplitude of the circadian oscillation in U2OS cells. To our knowledge, this is the first time that adenovirus infection was found to regulate circadian rhythms in cells.

cell biology↗

bioRxiv2022

Small CD4 mimetics sensitize HIV-1-infected macrophages to antibody-dependent cellular cytotoxicity

HIV-1 Envelope (Env) conformation determines the susceptibility of infected CD4+ T cells to Antibody Dependent Cellular Cytotoxicity (ADCC). Upon interaction with CD4, Env adopts more "open" conformations, exposing ADCC epitopes. HIV-1 limits Env-CD4 interaction and protects infected cells against ADCC by downregulating CD4 via Nef, Vpu and Env. Limited data exists however of the role of these proteins in downmodulating CD4 on infected macrophages and how this impacts Env conformation. While Nef, Vpu and Env are all required to efficiently downregulate CD4 on infected CD4+T cells, we show here that any one of these proteins is sufficient to downmodulate most CD4 from the surface of infected macrophages. Consistent with this finding, Nef and Vpu have a lesser impact on Env conformation and ADCC sensitivity in infected macrophages compared to CD4+T cells. However, treatment of infected macrophages with small CD4-mimetics expose vulnerable CD4-induced Env epitopes and sensitize them to ADCC.

microbiology↗

bioRxiv2022

Statistical Methods for Detecting Circadian Rhythmicity and Differential Circadian Patterns with Repeated Measurement in Transcriptomic Applications

Circadian analysis via transcriptomic data has been successful in revealing the clock output changes underlying many diseases and physiological processes. Repeated measurement design in a circadian study is prevalent, in which the same subject is repeatedly measured over time. Several methods are currently available to perform circadian analysis, however, none of them take advantage of the repeated measurement design. And ignoring the within-subject correlation from the repeated measurement could result in lower statistical power. To address this issue, we developed linear mixed model based methods to detect (i) circadian rhythmicity (i.e., Rpt_rhythmicity) and (ii) differential circadian patterns comparing two experimental conditions (i.e., Rpt_diff). Our model includes a subject-specific random effect, which will account for the within-subject correlation. Via simulations, we showed our method not only could control the type I error rate around the nominal level, but also achieve higher statistical power compared to other methods that cannot model repeated measurement. The superior performance of Rpt_rhythmicity and Rpt_diff were also demonstrated in two real data applications, including a human restricted feeding data and a human sleep restriction data. An R package for our methods is publicly available on GitHub to promote the application of our methods.

bioinformatics↗